Cardioplegic solution "infousa"

 

The invention relates to medicine, namely to the development of compositions of the solutions used during operations on the open heart. Polyionic buffer cardioplegic solution has an osmolarity (350±5) mOsm, contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, Asparaginate potassium, Asparaginate magnesium, mannitol, trisamin and water for injection in the following ratio of ingredients, wt.%: sodium chloride - 0,63-0,77; potassium chloride - 0,027-0,033; magnesium chloride shestibalny - 0,18-0,22; calcium chloride shestibalny - 0,009-0,011; potassium Asparaginate semi-aquatic - 0,20-0,24; magnesium Asparaginate chetyrehpolnye - 0,17-0,19; mannitol - 0,32-0,38; trisamin - 0,05-0,07; water for injection - else, while pH is 7.60.1 if 22C. Composition “Infosol provides a significant improvement in recovery of function and metabolism of the heart during reperfusion after cardiopulmonary bypass. 7 tab., 1 Il.

The invention relates to the field of medicine and is intended for use in operations on the open heart in conditions of artificial blood circulation.

Traditionally used in cardiac surgery cardioplegic solutions not pornstephanie. The result is a reduced recovery of the pumping function of the heart at the resumption of the circulation, which is complicated by the occurrence of reperfusion arrhythmias and heart failure. Therefore, the development of drugs that can reduce the risk of cardiovascular interventions, is an important task of modern molecular cardiology.

Currently, this problem is solved by the introduction of the cardioplegic solutions of natural antioxidants, natural metabolites, improving energy metabolism and stabilizing the sarcolemma of cardiomyocytes, as well as optimization of the ionic composition and pH of the solutions [1-3]. In recent years, in different laboratories, it was found that the addition to the standard cardioplegic solutions aspartic acid or its salts reduces the development of ischemic and reperfusion contracture and improves recovery of the heart after normothermal or hypothermic ischemia [4]. These beneficial effects are associated with the ability of the aspartic acid involved in the formation of energy in anaerobic and aerobic conditions and thus improve the energy status of the ischemic heart. The result of erodov and phosphocreatine during reperfusion [5, 6]. Among the most studied antioxidants used in magnesium and potassium crystalloid cardioplegia, is mannitol. It is used as scavenger for reduction of myocardial damage caused by the formation of oxygen free radicals, and to ensure the desired osmolarity of solutions [7, 8]. Fundamentally important indicator for the development of cardioplegic solutions is the preservation of their pH and buffer capacity. Experimental work performed in a number of leading laboratories have demonstrated long-term use trisamina compared with the use of sodium bicarbonate, histidine or imidazole to create a buffer systems in the pH range of 7.1 to 8.0 at 10-14[9]. Cardioplegic solutions with trisamino prevent the development of intracellular acidosis and reduce violations of the ion transport function of membrane ischemic cardiomyocytes [10]. The disadvantages of the above solutions, which are reported in the literature, should include 1) the difficulties associated with their preparation; 2) instability of the chemical composition and pH during prolonged storage; 3) insufficient recovery of contractile and pump function of the heart after the AC is t and pH to cardioplegic solution “Infosol is modified solution of Heilig. Thomas, containing trisamin [11]. It contains equimolar concentration of ions+and Mg2+(16 mm), low concentration of ions of CA2+(1.2 mm), close to the physiological concentration of Na+and CL-(120 mm and 153 mm, respectively) and trisamin (15 mm) for optimal buffer capacity. In experiments on isolated heart of rats, perfusion method Langendorf, evaluated the effectiveness of cardioplegic protection hearts with this cardioplegic solution, using as criteria the following indicators: 1 - indicator isovolumic heart, expressed by the product of maximum systolic blood pressure on heart rate; 2 - the removal of MB fraction of creatine kinase myocardial outflow during reperfusion; 3 - the content of high energy phosphates and lactate in the myocardium at the end of reperfusion. Use this solution for cardiac arrest resulted in a slight, though reliable, the improvement of the heart ((234)% compared to control hyperkaliemia cardioplegic solution containing 25 mm potassium chloride) and did not reduce the excretion MB-creatine kinase in the perfusion solution during reperfusion. At the end of the frame is included in the solution Heilig. Thomas, did not differ from control values. These data show that the use of the modified solution Heilig. Thomas as a cardioplegic means not effectively protects the function and metabolism of the myocardium from ischemic and reperfusion damage.

Despite the abundance of experimental data, indicating that the inclusion of the listed compounds in salt cardioplegic solutions, the optimal ratio of these additives and the need to simultaneously use remain outstanding.

The present invention is to solve the problem adequately protect the heart during cardioplegic stop operations. For this purpose we have developed salt cardioplegic solution in the original composition “Infousa” (PL.1) can significantly improve recovery of function and metabolism of the heart during reperfusion after cardiopulmonary bypass. It consists of components that are approved for medical use in the Pharmacological Committee of the Russian Federation.

Cardioplegic solution “Infousa” is a colorless, transparent, sterile fluid, designed for use PLA aorta in conditions of artificial blood circulation.

Research cardioprotective properties of the solution “Infosol performed on isolated hearts of rats male Wistar rats weighing 250-300 g by the standard method [5]. In anesthetized with urethane animals (1.0 to 1.5 mg/g body weight, V/b) extracted the heart and placed in chilled Krebs solution at 30-40 to a complete stop contractions. Then their was retrograde perfesional through the aorta for 10-15 min with Krebs solution, saturated with Carbogen (95% O2and 5% CO2) pH 7.4±0,1 at 37With constant perfusion pressure of 60 mm RT.article Then in the left atrium was entered cannula and proceeded to the perfusion in the running mode according to Neely for 20 min at a constant filling pressure of the left atrium 15 mm RT.article and the resistance to outflow of perfusion solution from the left ventricle 60 mm RT.article (initial state). Next conducted cardioplegic stopping at a temperature of 22C for 5 min in one of two cardioplegic solutions, control or “Infusion” with a constant bulk velocity (15,01.0) ml/min per 1 g wet tissue of the heart. As a control cardioplegic solution used a modified solution of the hospital of St. Thomas [11], ormaterials global ischemia. At the end of ischemia heart was reperfusion in working mode with Krebs buffer for 30 min at 37With simultaneous monitoring of physiological parameters.

Mean perfusion pressure in the aorta, the pressure in the cavity of the left ventricle were recorded using strain gauges P50, monitor SP 1405 and Registrar SP2010 Gould Statham. Aortic volume and coronary blood flow was measured with a graduated cylinder. On the basis of these indicators was calculated minute and stroke volume of the heart, his work is the product of cardiac output on average perfusion pressure. The intensity of the contractile function of the heart characterized by the product of developed left ventricular pressure, heart rate. The resistance of coronary vessels was estimated as the ratio of the mean perfusion pressure to the coronary flow.

At the end of reperfusion, the hearts were frozen nippers of Wollenberger cooled in liquid nitrogen. Frozen tissue is homogenized in cold 6% HClO4proteins precipitated with centrifugation, supernatant neutralized to pH 7.4 [5, 6]. Energy state reperfusion of the heart characterized by a content in protein-free tissue extracts of the historical methods [6, 12]. The dry weight of the fabric was determined by weighing a portion of the residue after extraction HClO4and drying at 110With during the night. The content of metabolites expressed in micromol per 1 g dry weight. Statistical analysis was performed using two-sided t-test, Student.

Method of preparation of cardioplegic solution “Infousa” for experiments on animals.

In 900 ml of water for injection with stirring at room temperature is dissolved in grams: sodium chloride - 7,08; potassium chloride - 0,30;

magnesium chloride shestibalny - 2,24; calcium chloride shestibalny - 0,26; asparagine potassium semi-aquatic - 2,16; asparagine magnesium chetyrehpolnye - 1,80; mannitol - 3,64; trisamin - 0,61. After complete dissolution of substances bring the solution pH to 7.6 with 222 N. HCl. The total volume of the solution was adjusted with water for injection to 1000 ml of the Solution is filtered through a filter of 0.45 μm firm Millipor” using the water-jet pump. Further, it is sterilized in an autoclave at 110C for 20 minutes thus Prepared solution preserves the specified pH, permanence and transparency in the course of one year when stored protected from light place at a temperature of the spruce working rat heart by Neely in comparison with the prototype - modified cardioplegic solution Heilig. Thomas. The effect of cardioplegic solutions on the indices of contractile and pumping functions of the heart are summarized in Table 3. In the initial state indicators contractile and pump function of the heart was not significantly different between the studied solutions. Within the first minute retrograde cardioplegic perfusion solution “Infousa” was observed cessation of pumping and contractile function of the heart. Thus, the effectiveness of cardiac arrest “Infousa” did not differ from the prototype. However, its application has greatly improved the recovery of most of the indicators of cardiac function during reperfusion. Protected “Infusion” heart to the end of reperfusion almost completely restored coronary flow to (98+3)% from the original values compared to (77+3)% when using cardioplegic solution Heilig. Thomas. This effect combined with a 2.6 times higher recovery stroke volume than in the case of the prototype. In the group of hearts stopped cardioplegic solution “Infousa”, throughout the period of reperfusion was observed more efficient recovery of cardiac output (see drawing). ETM indicator when using the reference solution. The results indicate a more complete recovery of contractile and pump function of the heart after a period of ischemia when you stop cardioplegic solution “Infousa”.

The effect of cardioplegic solution “Infousa” on the content of metabolites of energy metabolism, the level of lactate in the tissue of the heart and the integrity of the membrane of cardiomyocytes was assessed at the end of the period total normothermal ischemia and at the end of reperfusion. These data are shown in Table 4 and compared with the content of metabolites in the tissue of the heart in the initial state. After a period of ischemia in hearts stopped cardioplegic solution “Infousa”, the ATP content and RKF was significantly higher than that in the hearts perfoirmance cardioplegic solution comparison. So, when using “Infosol” the ATP content was reduced to (57,91,9)%, and in the case of the prototype to (12,7±6,3)% of the original. Level RKF was twice as high in the hearts of protected solution “Infousa”, and was (14,9±1,5)% vs. (7,5+2,5)% of baseline in control. Under the influence of “Infosol accumulation of lactate in the tissue of the heart at the end of ischemia was reduced by 1.5 compared to the prototype. At the end of reperfusion in hearts protected cardio and the use of the control cardioplegic solution. So, the ATP content was (70,44,8)% of baseline compared with (41,84,1)% in the case of the prototype. The content of RKF in hearts treated with “Infousa” at the end of reperfusion was restored to its original value and was (96,4±7,3)% of initial vs (76,8±5,2)% in the control. The content of total creatine (Kp) in hearts protected cardioplegic solution “Infousa”, was also higher than in the control hearts to the end of the reperfusion: it was (85,9±5,3)% of original value against (71,7of 3.5% in the control. The level of lactate in reperfusion myocardium in the control series by the end of reperfusion was 8 times higher than the original. At the same time in the hearts stopped cardioplegic solution “Infousa”, the content of lactate at the end of reperfusion did not significantly differ from the original. Thus, the analysis of metabolic parameters suggests that the use of cardioplegic solution “Infousa” provides the best recovery of aerobic metabolism in reperfusion the myocardium after a period of ischemia and contributes to a better preservation of the membrane of cardiomyocytes.

The efficacy of varying concentrations of the components Cardi is ical solutions containing lower and higher concentration of the main active ingredients of the drug is potassium chloride, magnesium chloride setevogo, calcium chloride setevogo, potassium Asparaginate semi-aquatic, magnesium Asparaginate chetyrehletnego, mannitol and trisamina. The osmolarity of these solutions were maintained the same as solution “Infousa”, by changing the concentration of sodium chloride. the pH of the solutions was unchanged and was 7.60.1 if 22C. as an example, in Table.5 shows the composition of the solutions “Infosol-1” and “Infosol-2”. The performance criteria of myocardial protection when using these modified solutions served and the time of the termination of the Electromechanical activity of the heart during cardioplegic perfusion and (b) the restoration of the indicators of cardiac function after semiii during subsequent reperfusion.

The Data Table.6 show that the reduction in concentrations of the major components of the cardioplegic solution “Infousa” below the minimum values listed in Table.1, in average 3 times increases the time required to fully stop the heart, thereby reducing the effectiveness of cardioplegia (“Infosol-1”). The increase in the concentration of components cardiopul the Influence of variation of the main active components cardioplegic preparation “Infosol on the degree of postischemic recovery of cardiac function in rats is shown in Table.7.

The decrease in concentrations of the major operating components of cardioplegic solution (“Infosol-1”) has led not only to a slower heart failure, but also significantly reduced the recovery of contractile performance and pumping functions of the heart, increased coronary resistance and diastolic indicator of elasticity by reperfusion. Cardioplegic solution with increased concentration of components (“Infosol-2”) even more increased the resistance of coronary vessels and stiffness of the myocardium during reperfusion. The consequence of this was the low recovery of coronary flow ($(547)% from baseline), minute and shock volume ($(133)% and (15±3)% of baseline values, respectively). Contractile function, estimated by the product of developed left ventricular pressure, heart rate, and the rate of external work of the heart when using cardioplegic solution “Infosol-2” recovered significantly worse than after cardioplegia with prototype or solution “Infousa” (PL.3, 7). These results indicate that the optimal functional myocardial protection from ischemic and repeopling tool able to improve the functional and metabolic recovery of the heart after global ischemia and reperfusion compared to current drugs.

Claims

Cardioplegic solution with osmolarity (350±5) mOsm containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, trisamin and water for injection, characterized in that it additionally contains asparagine potassium, Asparaginate magnesium and mannitol in the following ratio of ingredients, wt.%:

Sodium chloride 0,63-0,77

Potassium chloride 0,027-0,033

Magnesium chloride shestibalny 0,18-0,22

Calcium chloride shestibalny 0,009-0,011

Potassium Asparaginate semi-aquatic 0,20-0,24

Magnesium Asparaginate chetyrehpolnye 0,17-0,19

Mannitol 0,32-0,38

Trisamin 0,05-0,07

Water for injection

when 22With a pH of 7.6±0,1 Else

 

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